{60 ,{60 -dialkanoyloxyacetyl penicillanic acid derivatives

ABSTRACT

Novel penicillin type compounds are prepared by the Alpha , Alpha -dialkanoyloxyacetylation of amino substituted penicillanic acid derivatives. The compounds are useful as antibacterial agents.

United States Patent McCaully 1 July 18, 1972 54] a,a-DIALKANOYLOXYACETYL [56] References Cited PENICILL C ACID DERIVA UNITED STATES PATENTS [72] Invent Mccauuy Malvem' 3,325,477 6/1967 Fosker et al. ..260/239.l [73] Assignee: American Home Products Corporation,

N Y k N Y Primary Examiner-Nicholas S. Rizzo Attorney-Andrew Kafko, Joseph Martin Weigman, Dwight J. [22] Filed: May 1970 Potter, Vito Victor Bellino and Robert Wiser [211 App]. No.: 37,910 ABSTRACT Novel penicillin type compounds are prepared by the a,a-dial- [52] 424/271 kanoyloxyacetylation of amino substituted penicillanic acid [51] 99/16 derivatives. The compounds are useful as antibacterial agents. [58] Field of Search ..260/239.]

3 Claims, No Drawings a ,a-DIALKANOYLOXYACETYL PENICILLANIC ACID DERIVATIVES wherein R is selected from the group consisting of o OR;

-NH CH and 0 0 000m -NH -cH NH-r'i-o R is selected from the group consisting of hydrogen and alkali metals; R is selected from the group consisting of hydrogen and lower alkyl; R is lower alkyl.

The invention also includes the hydrated and monohydrate forms of the compounds disclosed herein.

When used herein and in the appended claims, the term (lower)alkyl" contemplated hydrocarbon radicals, straight and branched, of from about one to about six carbon atoms, illustrative members of the group being methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, n-pentyl, n-hexyl and the like.

Compounds of FORMULA I may be prepared by contacting an a -dialkanoyloxyacetylhalide with an appropriate amino substituted penicillanic acid derivative according to the following reaction:

OCORz NH1 Y-C 0-C OCORa OCOR:

NH-CO-CH HY OCOR:

anhydride are removed by co-distillation with 100 ml. of.

toluene. The residue is dissolved in 350 ml. of methylene chloride and treated with 180 ml. (298 g.) of thionyl chloride. The mixture is then heated at gentle reflux for about 20 minutes and evaporated on a rotary evaporator. An additional 100 ml. of methylene chloride is added and re-evaporated to remove traces of volatile reactants. The homologs may be obtained in a similar manner.

The novel compounds of the invention are antibacterial agents useful in treating bovine mastitis and other infections amenable to therapy with penicillanic acid derivatives such as benzylpenicillin. They are also useful as growth promoters for ruminant animals such as cattle. The compounds of the invention are also useful for the inhibition of Staph. aureu, Smith at a concentration of less than 250 micrograms/ml. when applied in an aqueous vehicle.

' 374-44, (acid OH), 5.65-5.78

While the invention is described in its broadest terms herein-above the following examples are added to set forth specific working embodiments of the invention.

EXAMPLE! 6-(2,Z-Dihydroxyacetamido)penicillanic acid, diacetate, sodium salt To 10.81 g. of -aminopenicillanic acid slun'ied in ml. of methylene chloride is added a solution of 9.75 g. of a diacetoxyacetyl chloride dissolved in 50 ml. of methylene chloride. The mixture is stirred at 26 C. for 2.5 hours and filtered from the undissolved solid. The filtrate is washed three times with water and then dried by passage through cotton. The yellow, oily residue that remains afier evaporation of the solvent is dissolved in ethanol and allowed to stand for 12 hours. The ethanol is removed on a rotary evaporator, and the residue dissolved in ether-acetonitrile is treated with sodium 2-ethylhexanoate. The solid that separates is washed thoroughly with ether to yield the title product, m.p. i2ll 25 C. dec.

The infrared spectrum (KBr) of the product had bands at 3.00 #(NI-I), 5.68 (broad, B-lactam and ester C 0), 5.94; (amide (C 0), 6.14 and 7.29: (COO9), and 6.6l/(amide II).

EXAMPLE II SO Evaporation of the solvent yields 4.2 g. of 6-[2-(2,2-

dihydroxyacetamido)-2-phenylacetamido]penicillanic acid, diacetate, dihydrate (m.p. 78-80C.) as a light yellow solid.

Anal. Calcd for C l-I N O S-2H C: C, 48.61; H, 5.38; N,

Found: C, 48.99; H, 4.77; N, 7.66. The infrared spectrum (KBr) had bands at 3.09 ,,'(Nl-I), (broad; B-lactam, ester, and C O), 6.05,, (amide C O), and 6.6 (amide II).

EXAMPLE III By an analogous procedure, the following compounds are prepared:

EXAMPLE IV By an analogous procedure, the following compounds are prepared:

R26 0 CH3 1. A compound of the formula R is selected from the group consisting of hydrogen and alkali metals; R is selected from the group consisting of hydrogen and (lower)alkyl; R is (lower)alkyl. H 2. A compound as defined in claim 1 which is 6-(2,2- I 3 dihydroxyacetamido)penicillanic acid, diacetate, sodium salt. 3. A compound as defined in claim 1 which is 6-[2-(2,2- dihydroxyacetamido)-2-phenylacetamido]penicillanic acid, diacetate, dihydrate.

wherein R is selected from the group consisting of 5 r c a: 

2. A compound as defined in claim 1 which is 6-(2,2-dihydroxyacetamido)penicillanic acid, diacetate, sodium salt.
 3. A compound as defined in claim 1 which is 6-(2-(2,2-dihydroxyacetamido)-2-phenylacetamido)penicillanic acid, diacetate, dihydrate. 